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$100m to bolster psychiatric research

Cambridge institute seeks answers in genes

The Broad Institute, the genomics powerhouse in Cambridge, announced yesterday that it will receive what it believes is the biggest gift ever for psychiatric research to a single US institution: $100 million to decipher the genetics of severe mental illnesses.

The money comes from the Stanley Medical Research Institute , a family philanthropy based in Maryland. It will be used largely to gather and analyze thousands of DNA samples from people with schizophrenia and bipolar disorder, in hopes of determining the complex genetics behind the diseases.

Only in the last year or so has gene-scanning technology reached the point that scientists think that aim is realistic, said Dr. Edward Scolnick , who oversees the Broad's psychiatric research. Researchers at the Broad and elsewhere are also using these genomic tools to make inroads on cancer, diabetes, and other diseases.

For mental illness, it could take several years to determine the key genetic risk factors, Scolnick said. But once that is done, "You can start developing new approaches for diagnosis, new targets for treatment, new understanding of which drugs to use in which people, and turn it into a rational science. That's the Holy Grail."

It has long been clear that schizophrenia and bipolar disorder, which afflict more than 6 million Americans, run in families. But the specific genes involved have proven largely elusive.

The symptoms tend to vary so greatly among patients that schizophrenia, for example, may actually be a handful of different diseases. Complicating matters further, these disorders are believed to stem from multiple genes that might be different from patient to patient, along with factors in a patient's environment.

Given that complexity, researchers believe they need many DNA samples to pick up the tricky genetic signals: perhaps as many as 10,000 for each disease, along with 10,000 from people without the disease for comparison, Scolnick said.

That DNA then needs to be scanned in its entirety for genes correlated to the disease, which is where the Broad's expertise comes in. The institute has been developing ever-faster and cheaper methods for genomic analysis, and can now scan a patient's sample for half-a-million genetic variations at once. In a couple of months, said Eric Lander , the Broad's director, that will be up to a million.

"If you're looking for a needle in a haystack, and you can sift the whole haystack, you'll find the needle," Lander said.

Other research groups have begun tackling the genomics of serious mental illnesses, and the National Institute of Mental Health maintains a huge repository of DNA from people with mental illness, said Dr. Tom Insel , the federal institute's director. But only recently has it become clear from work with other complex diseases that to crack the genetics of bipolar disorder or schizophrenia, many more samples are needed than had been thought, he said.

The gift to the Broad "is exactly the right thing at the right time at the right place," Insel said. "We now have the ability to do a lot of the genetics we couldn't do two years ago, and there's probably no better place than the Broad to do that."

The gene-scanning results will be posted publicly, he said, so that all researchers will have access to the data. After the initial sweeping scans of a patient's full DNA, researchers will then need to "drill down" into targeted areas of DNA to piece apart where exactly the genetic problems lie, he said.

Then, researchers say, comes the really hard part: figuring out how the genes act to produce the disease.

The Broad, a joint institute of Harvard and the Massachusetts Institute of Technology, will be using "the full armamentarium of modern genomics," Lander said.

Along with gene-scanning, that will include the rapid automated screening of hundreds of thousands of chemical compounds to see if they might prove helpful in treating the diseases, and a technique called RNA interference that can silence any particular gene so researchers can gauge the gene's effects. The aim, he said, is to "lay bare the molecular and cellular basis of psychiatric disease."

The Broad's approach has begun to bear fruit of late with other diseases, Lander said. For example, he said, up until a year ago, only two genes were known risk factors for Type 2 diabetes; now, the Broad has brought that number up to nine. There has been notable progress on the genetics of cancer, macular degeneration, and other diseases as well.

The Broad needed no hard sell to get the money. Scolnick said that last summer, he had begun discussing with the Stanley institute, which funds research on mental illness, whether it might increase the donations it had been providing to the Broad.

"I'd asked for some modest increases," he said, "and they came back after my proposal and said, 'We'd really like to do more, what can you realistically use?"'

The Broad's new Stanley Center for Psychiatric Research will receive $10 million a year for 10 years, out of the Stanley institute's $40-million-a-year operating budget, said Dr. Michael Knable , the institute's executive director. Previously the Broad had been spending only about $500,000 a year on psychiatric work.

The Stanley Medical Research Institute has an endowment of over $300 million, and says it is the biggest private source of philanthropic support for psychiatric research in the world.

Ted Stanley, 75, founded MBI Inc., a direct marketer of books, jewelry, and collectibles; he and his wife, Vada, fund the institute.

Knable, asked what results he expected, said: "I'm thinking that on the one hand, within 10 years we should be able to predict with pretty good accuracy who is at risk for schizophrenia before they get it," he said.

"And number two, I think we'll have new drugs entering the marketplace that are novel," not new versions of "the same old stuff we've had since the 1950s."

Carey Goldberg can be reached at